GSK-J4 combined with mitomycin C as a novel combination therapy for non-muscle invasive bladder cancer

Abstract

Event Abstract Back to Event GSK-J4 combined with mitomycin C as a novel combination therapy for non-muscle invasive bladder cancer Anna-Maria Caridis1, Callum Perkins1, Alessandro Di Maio1, Douglas Ward1, Udo Oppermann2, Chas Bountra2, Farhat Khanim1 and Richard Bryan1* 1 University of Birmingham, United Kingdom 2 University of Oxford, United Kingdom Background Urothelial bladder cancer (UBC) is the 7th most common cancer in Western societies and non-muscle invasive bladder cancer (NMIBC) represents 75-80% of incident cases. The current standard of treatment of NMIBC comprises intravesical mitomycin C (MMC) or Bacillus Calmette-Guérin (BCG); however, <50% of patients enter remission and ~20% of NMIBC patients eventually die from their disease. Six years of unstable BCG supply globally have created an urgent unmet need for new agents to treat NMIBC. Epigenetic changes are common in UBC and are associated with worse outcomes. In collaboration with the Structural Genomics Consortium (Oxford, UK), we screened a panel of epigenetic modulators for their activity against UBC cell lines and identified GSK-J4, a histone lysine demethylase inhibitor. Materials and Methods UBC cell lines (T24, SW780, VM-CUB1 and HBCLS2) were treated with either continuous or 1 hour pulses of MMC and/or GSK-J4. Cell viability and IC50 values were determined by CellTiter-Blue assay. Apoptosis and cell cycle were analysed using flow cytometry. Growth inhibition by GSK-J4 was also measured in 3D spheroids. Results GSK-J4 alone was able to reduce the viability of UBC cell lines in a dose-dependent fashion. Furthermore, when GSK-J4 was given in combination with MMC, it increased the efficacy of the latter, further reducing cell viability. Further experiments demonstrated that a 1hr pulse, mirroring a 1hr intravesical exposure, was sufficient to induce significant cell death. GSK-J4 arrested cells in the G1 cell cycle phase without induction of apoptosis. Finally, GSK-J4 was able to inhibit the growth of bladder cancer spheroids. Conclusions We have demonstrated that treatment of UBC cell lines with a single 1 hour pulse of GSK-J4 combined with MMC, results in significant cell death and enhanced killing compared to either agent alone. Furthermore, addition of GSK-J4 allows dose-reduction of MMC. Keywords: UTX, JMJD3, epigenetics, 3D spheroids, adjunctive chemotherapy Conference: Bladder Cancer Translational Research Meeting, London, United Kingdom, 29 Mar - 29 Mar, 2019. Presentation Type: Oral Topic: Development of personalised treatment Citation: Caridis A, Perkins C, Di Maio A, Ward D, Oppermann U, Bountra C, Khanim F and Bryan R (2019). GSK-J4 combined with mitomycin C as a novel combination therapy for non-muscle invasive bladder cancer. Front. Oncol. Conference Abstract: Bladder Cancer Translational Research Meeting. doi: 10.3389/conf.fonc.2019.01.00010 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 28 Feb 2019; Published Online: 27 Sep 2019. * Correspondence: MD, PhD. Richard Bryan, University of Birmingham, Birmingham, United Kingdom, R.T.Bryan@bham.ac.uk Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Anna-Maria Caridis Callum Perkins Alessandro Di Maio Douglas Ward Udo Oppermann Chas Bountra Farhat Khanim Richard Bryan Google Anna-Maria Caridis Callum Perkins Alessandro Di Maio Douglas Ward Udo Oppermann Chas Bountra Farhat Khanim Richard Bryan Google Scholar Anna-Maria Caridis Callum Perkins Alessandro Di Maio Douglas Ward Udo Oppermann Chas Bountra Farhat Khanim Richard Bryan PubMed Anna-Maria Caridis Callum Perkins Alessandro Di Maio Douglas Ward Udo Oppermann Chas Bountra Farhat Khanim Richard Bryan Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.